Using brain activity to identify risk for disorders

September 16, 2001

Alcoholism is a genetically complex disorder. That is, it is produced by an unknown number of genes that interact in an unknown fashion with one another and with an unknown variety of environmental factors. To dispense with the mystery, individuals who wish to identify their risk for developing alcoholism can undergo a noninvasive measure of brain electrical activity called P300 event-related potential (ERP), one of the few brain measures associated with risk for alcoholism. A study in the September issue of Alcoholism: Clinical & Experimental Research examines the variation in P300 amplitude in individuals with co-existing alcohol-use and anxiety disorders.

"We predicted," said Mary-Anne Enoch, a staff scientist in the Laboratory of Neurogenetics at the National Institute on Alcohol Abuse and Alcoholism and lead author of the study, "based on the results of previously published studies, that alcoholics would have low P300, anxiety disorder subjects would have high P300, but we could not predict which way alcoholics with anxiety disorders would go." Some of their findings were expected, while others were not.

"Even though our subjects had less severe forms of alcoholism and anxiety disorders, we nonetheless found that alcoholics had lower P300 amplitudes, and subjects with anxiety disorders had higher P300 amplitudes. When we looked at the subgroups, the results were much more dramatic. We found that it was the alcoholics with co-morbid anxiety disorders who had the lowest P300 amplitudes. Our study showed that the effects of alcoholism vulnerability on P300 amplitude wiped out or dominated the effect of anxiety vulnerability on P300 amplitude. It is often thought that people with anxiety disorders are more susceptible to alcoholism as they might tend to 'self-medicate'. However, our results suggest that P300 amplitude may distinguish which anxious individuals are vulnerable to becoming alcoholic."

"There are many different ways that someone can be at risk for developing alcoholism," concurred Cindy L. Ehlers, associate professor of neuropharmacology at The Scripps Research Institute, "and one of them is to have an anxiety disorder. Alcohol is an anxiolytic (or anti-anxiety) agent. People who have anxiety can get relief from drinking. In fact, this is referred to as 'relief drinking.' While it may seem confusing that the group with both alcoholism and anxiety disorders have the lowest P300 amplitudes, it's entirely plausible that someone with an anxiety disorder who does not develop alcoholism may have protective factors against the development of alcoholism that mediate their high risk. In other words, having a higher P300 may be a measure of a protective factor." Which, alternately, means that having the lowest P300 may indicate the most severe of risk factors. Either perspective both supports and extends P300 research that began in the early 1980s.

An individual's electroencephalogram (EEG) - a recording of the continuous electrical activity going on in a person's brain - is like a distinctive fingerprint. Even when we're unaware of it, our brains are constantly on the alert for new stimuli or unusual changes in our immediate environment. If, for example, we are listening to the sound of rain and a clap of thunder interrupts, our brain will respond by producing a very brief electrical wave in our EEG. This is called an event-related potential (ERP). The maximum amplitude of the electrical wave occurs at around 300 millisecs after the onset of the stimulus, which is why it is called the P300 ERP.

There exist a number of ways to measure ERPs in the laboratory. A subject might be shown the same picture on a computer screen again and again, but occasionally, and randomly, a different picture will appear and the subject will produce a P300 ERP in response to the rare stimulus. Or, a subject might listen to a stream of low-pitched sounds, interrupted by a high-pitched sound, to which their brain will respond with a P300 ERP. The more unusual or rare the stimulus, the larger the amplitude of the P300.

The P300 is a measure of the way the brain pays attention and discriminates between potentially important and non-important stimuli. An individual inherits some aspects of their P300. Alcoholism is also heritable. Some alcoholics react differently to stimuli than do non-alcoholics; the amplitude of their P300 response tends to be lower than that of non-alcoholics. Alcoholics with a strong family history of alcoholism tend to have the lowest P300 amplitudes of all. Even some non-drinking children of alcoholics have low P300 amplitudes. This suggests that a low P300 is not caused by drinking but is inherited. It also suggests that a person with a low P300 may be at risk of becoming an alcoholic.

"Anxious individuals tend to be less relaxed," said Enoch, "more alert and have heightened awareness. They are more likely to respond vigorously to changes in the environment. You could say that they are more 'jumpy'. They would therefore be expected to produce bigger P300 amplitude responses. Studies have also shown that people who have an anxiety disorder but are not anxious at the time of testing have high P300 amplitudes, suggesting that high P300 may be a risk factor for anxiety disorders."

Enoch added that because alcoholism is a complex disease, it is important to examine subgroups of alcoholics in which alcoholism interacts with other psychiatric disorders, such as major depression, anxiety disorders and antisocial personality disorder. "Our study found that low P300 amplitude was a marker for alcoholism co-morbid with anxiety disorders," she said, "but not for non-anxious alcoholism. Is P300 a marker for other alcoholism subgroups, and if so, what are the underlying factors that link these groups? These questions need to be addressed."

"Alcoholism comes in many different forms," said Ehlers, "because different people have different risks. Someone who has conduct disorder and is at risk for alcoholism probably has a different set of genes coding for this vulnerability than someone who has anxiety disorder and is at risk for alcoholism, even though they both have alcoholism." She agreed that it is imperative to understand the different subgroups of alcoholism before discovering which genes are "coding" for particular disorders.

Yet, she added, "it is especially important for people to realize that risk doesn't equate disorder. Getting alcohol dependence is like going through a pinball machine. The ball bounces off of a number of different risk and protective factors. In the end, the accumulation of all of these 'encounters,' plus intangible factors such as free will, religion, culture, and family lead to a final phenotype. High risk doesn't equal alcoholism, however, an individual who has risk factors in his or her life needs to take greater care regarding their drinking behavior."
Co-authors of the Alcoholism: Clinical & Experimental Research paper included: Kenneth V. White, Claudia R. Harris, and David Goldman of the Laboratory of Neurogenetics at the National Institute on Alcohol Abuse and Alcoholism; and John W. Rohrbaugh of the Department of Psychiatry at Washington University School of Medicine.

Alcoholism: Clinical & Experimental Research

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